Rhynchophylline prevents cardiac dysfunction and improves survival in lipopolysaccharide-challenged mice via suppressing macrophage I-κBα phosphorylation

Myocardial dysfunction is a common complication during sepsis and significantly contributes to the mortality of patients with septic shock. However, none of the available therapeutic strategies proven to be effective in patients with severe sepsis are designed specifically to target myocardial dysfunction. The purpose of the present study is to investigate the effect of rhynchophylline (Rhy) on LPS-induced myocardial dysfunction in mice. We found that pretreatment with Rhy significantly improved cardiac systolic dysfunction, increased stroke volume and cardiac output in mice challenged with LPS. LPS induced cardiac inhibitor-κBα (I-κBα) phosphorylation, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA expression, and in turn increased cardiac TNF-α and IL-1β protein production, all of which were attenuated by pretreatment with Rhy. Immunohistochemistry revealed that TNF-α was found in infiltrated macrophages (F4/80+) and myocardium, and Rhy reduced TNF-α immunostaining in cardiac infiltrated macrophages in LPS-challenged mice. Furthermore, Rhy inhibited LPS-induced I-κBα phosphorylation and TNF-α production in cultured mouse peritoneal macrophages, but not in neonatal mouse cardiomyocytes. Pretreatment with Rhy significantly decreased the mortality of LPS-challenged mice. These results indicate that Rhy reduces cardiac dysfunction and improves survival via suppression of macrophage I-κBα phosphorylation in LPS-challenged mice, and suggest that Rhy may be a potential agent for the treatment of septic cardiac dysfunction.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Rhynchophylline inhibited LPS-induced I-κBα phosphorylation in macrophages. ► Rhynchophylline did not block LPS-induced TNF-α production in cardiomyocytes. ► Rhynchophylline inhibited LPS-induced cardiac I-κBα phosphorylation. ► Rhynchophylline inhibited LPS-induced cardiac TNF-α and IL-1β expression. ► Rhynchophylline improved cardiac dysfunction and survival in LPS-challenged mice.